The prototypical analgesic, morphine, is widely employed clinically. It is generally recognized that morphine and a majority of structurally related analgesics mediate their action via mu opioid receptors (MOR). In this regard, the use of morphine and other mu-selective analgesics is problematic in the treatment of chronic inflammatory pain due to adverse effects that develop with chronic use.1 
As members of the class A group of G protein-coupled receptors (GPCRs), three of the four members of the opioid receptor family mu (MOR), delta (DOR), and kappa (KOR) are activated by both the endogenous opioid peptide family and opiate structures related to morphine.2 
The existence of opioid receptor heteromers in cultured cells,3 and possibly in vivo, has offered new approaches to development of analgesics for the treatment of chronic pain without attendant side effects. As it is known that tolerance and/or dependence to chronic morphine treatment can be eliminated either by blocking DOR with a delta antagonist4 or blocking DOR biosynthesis,5,6 these studies are consistent with the MOR-DOR heteromer as a target for the mediation of these effects. Subsequent reports suggested that tolerance and dependence of mu opioid analgesics are likely due to targeting of MOR-DOR heteromer rather than a MOR homomer.7,8 Thus, differences in signaling and trafficking pathways between the MOR-DOR heteromer and MOR homomer may contribute to the absence of tolerance and physical dependence in mice devoid of functional DOR.9,10 
An approach based on the results of the above studies led to the development of a bivalent ligand (MDAN-21) that contains mu agonist and delta antagonist pharmacophores, produced potent antinociception in mice without tolerance or dependence.11 It is noteworthy that the bridging of protomers by MDAN-21 was found to prevent internalization of MOR and DOR.12 
There are a number of reports that opioid ligands targeting heteromers other than MOR-DOR do not display the same adverse effect profiles as morphine. For example, chronic administration of NNTA,13 an opioid agonist that is selective for MOR-KOR heteromer, exhibits no tolerance or dependence. Similarly, INTA, a ligand that preferentially activates both MOR-KOR and DOR-KOR also is devoid of these side effects.14 Additionally, the aversive effect generally associated with kappa agonists is greatly diminished with NNTA and totally eliminated with INTA, suggesting that it is the combination of protomers in the heteromer that governs the nature and intensity of the adverse effects.
Based on reports on the role of beta-arrestin in agonist-induced biasing of GPCRs,15 it has been suggested that alteration or inhibition of recruitment of this scaffolding protein by the heteromer following activation may afford biased signaling pathways that could lead either to diminution or enhancement of adverse effects that would depend on the constitution of both the agonist and the heteromer.
The design and antinociceptive activity of a bivalent ligand (MMG22)16 which contains both mu opioid agonist and metabotropic glutamate receptor-5 antagonist (mGluR5) pharmacophores has been reported. As an opioid agonist that targets the MOR-mGluR5 heteromer, MMG22 is both exceptionally potent and devoid of adverse effects upon chronic spinal administration to mice with inflammatory pain. Significantly, MMG22 is nearly 40,000-fold more potent than a co-administered mixture of monovalent mu agonist and mGluR5 antagonist. Thus, a bivalent ligand capable of bridging the protomers of a heteromer is vastly superior to monovalent ligands. Some possibilities that could contribute to the phenomenal potency could include changes in trafficking and lack of tolerance. Subsequent studies on mice with fibrsarcoma revealed that the antinociception of MMG22 became more potent with cancer progression and, 21 days after implantation, MMG22 was 2.6 million-times more potent than morphine.17 
Given the unusually high potency of MMG22 in targeting the MOR-mGluR5 heteromer and absence of adverse effects, a similar approach for targeting a putative MOR heteromer containing a CCR5 protomer. CCR5 is one of the ten known CC chemokine receptors in the class A family of GPCRs that is a member of the four subfamilies of chemokines (CC, CXC, CX3C, XC).18 
Inflammation promotes release of chemokines whose signaling has been implicated in the pathogenesis of neuroinflammatory processes, including neuropathic pain.19 As MOR and CCR5 are present in neurons, glia, and co-localized in pain processing areas,20,23 it is possible that MOR-CCR5 heteromer exists in vivo as well, in view of its presence in cultured cells.24,25 Given that CCR5 is expressed on immune cells that include microglia, and is an important co-receptor involved in HIV-1 entry into immune cells,24 it has been an important target in the treatment of neuroAIDS.
Accordingly, there is a need for therapeutic agents that treat pain (e.g., chronic inflammatory pain, neuropathic pain and HIV-induced neuropathy).